The overall objective of this proposal is to study the epigenetic factors that favor, modify or inhibit the expression of the malignant phenotype of undifferentiated embryonic cells and stem cells of teratocarcinoma. In a continuation of our present studies we plan to investigate the differentiation and growth of normal embryonic cells and embryonal carcinoma cells transplanted into adult hosts or injected into developing embryos as well as under controlled conditions in vitro. Differentiation and growth of embryonic cells and embryonal carcinoma cells will be primarily investigated as a function of interaction between the undifferentiated cells and somatic cells in the adult or embryonic cells in utero and in vitro. Chemical and biological approaches to modify the differentiation will be pursued. The genome of the embryonal cells will be manipulated to determine the effects of genomic alterations on expression of malignant phenotype. Differentiation and/or expression of onco-embryonic phenotype will be monitored by light and electron microscopy using enzyme histochemical and immunocytochemical techniques. These studies are intended to increase our understanding of basic mechanisms accounting for the transition of normal embryonic cells into stem cells of teratocarcinoma and the epigenetic control of malignancy in general.